title: Effect of statin therapy on mortality in patients with ventilator-associated pneumonia: a randomized clinical trial.
abstract: OBJECTIVE
  Observational studies have reported that statin use may be associated with improved outcomes of various infections. Ventilator-associated pneumonia (VAP) is the most common infection in the intensive care unit (ICU) and is associated with substantial mortality.
  
  
  OBJECTIVE
  To determine whether statin therapy can decrease day-28 mortality in patients with VAP.
  
  
  METHODS
  Randomized, placebo-controlled, double-blind, parallel-group, multicenter trial performed in 26 intensive care units in France from January 2010 to March 2013. For power to detect an 8% absolute reduction in the day-28 mortality rate, we planned to enroll 1002 patients requiring invasive mechanical ventilation for more than 2 days and having suspected VAP, defined as a modified Clinical Pulmonary Infection Score of 5 or greater. The futility stopping rules were an absolute increase in day-28 mortality of at least 2.7% with simvastatin compared with placebo after enrollment of the first 251 patients.
  
  
  METHODS
  Participants were randomized to receive simvastatin (60 mg) or placebo, started on the same day as antibiotic therapy and given until ICU discharge, death, or day 28, whichever occurred first.
  
  
  METHODS
  Primary outcome was day-28 mortality. Day-14, ICU, and hospital mortality rates were determined, as well as duration of mechanical ventilation and Sequential Organ Failure Assessment (SOFA) scores on days 3, 7, and 14.
  
  
  RESULTS
  The study was stopped for futility at the first scheduled interim analysis after enrollment of 300 patients, of whom all but 7% in the simvastatin group and 11% in the placebo group were naive to statin therapy at ICU admission. Day-28 mortality was not lower in the simvastatin group (21.2% [95% CI, 15.4% to 28.6%) than in the placebo group (15.2% [95% CI, 10.2% to 22.1%]; P = .10; hazard ratio, 1.45 [95% CI, 0.83 to 2.51]); the between-group difference was 6.0% (95% CI, -3.0% to 14.9%). In statin-naive patients, day-28 mortality was 21.5% (95% CI, 15.4% to 29.1%) with simvastatin and 13.8% (95% CI, 8.8% to 21.0%) with placebo (P = .054) (between-group difference, 7.7% [95%CI, -1.8% to 16.8%). There were no significant differences regarding day-14, ICU, or hospital mortality rates; duration of mechanical ventilation; or changes in SOFA score.
  
  
  CONCLUSIONS
  In adults with suspected VAP, adjunctive simvastatin therapy compared with placebo did not improve day-28 survival. These findings do not support the use of statins with the goal of improving VAP outcomes.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01057758.
authors.affiliation: Assistance Publique-Hôpitaux de Marseille, Hôpital Nord, Réanimation des Détresses Respiratoires et des Infections Sévères UMR-CNRS 7278, Aix-Marseile Université, Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Papazian
authors.forename: Antoine
authors.initials: A
authors.lastname: Roch
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Charles
authors.forename: Christine
authors.initials: C
authors.lastname: Penot-Ragon
authors.forename: Gilles
authors.initials: G
authors.lastname: Perrin
authors.forename: Philippe
authors.initials: P
authors.lastname: Roulier
authors.forename: Philippe
authors.initials: P
authors.lastname: Goutorbe
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Lefrant
authors.forename: Sandrine
authors.initials: S
authors.lastname: Wiramus
authors.forename: Boris
authors.initials: B
authors.lastname: Jung
authors.forename: Sébastien
authors.initials: S
authors.lastname: Perbet
authors.forename: Romain
authors.initials: R
authors.lastname: Hernu
authors.forename: André
authors.initials: A
authors.lastname: Nau
authors.forename: Olivier
authors.initials: O
authors.lastname: Baldesi
authors.forename: Jerome
authors.initials: J
authors.lastname: Allardet-Servent
authors.forename: Karine
authors.initials: K
authors.lastname: Baumstarck
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Jouve
authors.forename: Myriam
authors.initials: M
authors.lastname: Moussa
authors.forename: Sami
authors.initials: S
authors.lastname: Hraiech
authors.forename: Christophe
authors.initials: C
authors.lastname: Guervilly
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Forel
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D053717:Pneumonia, Ventilator-Associated / Q000188:drug therapy*; D012121:Respiration, Artificial; D019821:Simvastatin / Q000627:therapeutic use*; D016019:Survival Analysis
chemical_list: D000900:Anti-Bacterial Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin